Dihydropyridine calcium ion channel blockers are agents for treating cardiovascular diseases since 1970s. They selectively block the Ca2+ influx in the L-type or/and T-type calcium ion channels and reduce the intracellular Ca2+ concentration by binding to protein receptor(s) so as to alter the cardiovascular function and exert a protective effect on heart and brain blood vessels. Dihydropyridine calcium ion channel blockers have high blood vessel selectivity, remarkable hypotensive effect, and wide applicability, and are therefore widely used clinically and become the first choice for the hypotensive agents.
Dihydropyridines are the most commonly used calcium ion channel blockers for treating high blood pressure. According to the duration of action and the pharmacological characteristics thereof, dihydropyridines can be divided into three generations (Expert Opin. Drug Metab. Toxicol. (2009) 5(8): 981-987). The first generation is the traditional short-acting blockers; and the representive agent is nifedipine. This kind of agents has a short duration time and a strong peripheral vasodilation effect, and causes facial flush, reflex tachycardia and peripheral edema. This kind of calcium ion channel blockers can produce a fast and substaintial hypotensive effect, and cause a large fluctuation in the blood pressure. Sometimes, it may increase the risk of the heart complication (e.g. myocardial infarction), and therefore has a remarkable negative effect on heart and increases the risk of heart attack for the hypertension patient. In addition, it may also cause reflective sympathetic excitation, resulting in the increase in myocardial oxygen consumption, and may easily induce arrhythmia and myocardial infarction. The second generation is the intermediate-acting blockers, which prolong the duration time of the blocking effect on the calcium ion channels and lower the acute vasodilation effect. One class is the sustained formulation of the first generation agents, and the representive agents include nifedipine controlled-release tablet (nifedipine GITS). Another class is the long-acting calcium ion channel blockers, and the representive agents include amlodipine. For this class of agents, the side effects caused by the acute vasodilation are almost disappeared, and the hypotensive effect lasts for more than 24 hours. The main side effect of the second generation agents is the peripheral edema caused by the continous peripheric vasodilation. The aim for the calcium ion channel blockers of the third generation is to maintain the long-acting hypotensive effect, while further descrease the occurrence of peripheral edema. The representive agents include barnidipine, lercanidipine, manidipine and the like. In comparison with amlodipine, this kind of agents has a longer acting effect and an increase in tolerance.
As the development in the L-type calcium ion channel blockers, both the pharmacological activity and the pharmacokinetic characterics of calcium ion channel blockers have been improved. However, the various side effects caused by the long term administration have not been overcome yet.
It was found in research that the T-type calcium ion channels are expressed in various arteries and veins. Being different from the L-type calcium ion channels, the T-type calcium ion channels participate in the adjust of the microcirculation, which has an important role in adjusting blood pressure, renal perfusion and coronary flow (J Pharmacol Sci (2005) 99: 214-220). In the renal microcirculation, the L-type calcium ion channels are mainly located in afferent glomerular arteriole, and the inhibition on the activity of L-type calcium ion channels can easily cause the side effect of vascular dilated edema. However, the T-type calcium ion channels are located in both afferent glomerular arteriole and efferent glomerular arteriole, and the inhibition on the T-type calcium ion channels can improve the microcirculation through the balanced hydrostatics, increase the glomerular filtration rate and decrease the vascular dilated edema without an influence on the glomerular internal pressure, and therefore have a long-term protective effect on kidney. On the other hand, the T-type calcium ion channel blockers can also adjust heart beat and regulate blood flow rate, and therefore have a protective effect on heart.
The L-type and T-type dual calcium ion channel blockers have the functions of decreasing the blood pressure, slowing down the tachycardia, and reducing the edema occurrence, and therefore have a protective effect on heart and kidney (Hypertension. 2009; 53: 592-594). It is found in the clinical research that the L-type and T-type dual calcium ion channel blocker mibefradil is an effective hypotensive and antiischemic agent. It can reduce the side effects caused by the conventional calcium ion channel blockers, relax the vascular smooth muscle, reduce the heart rate without decreasing the myocardial contractile force, and improve the heart function (Exp. Opin. Invest. Drugs (1997) 6(5): 569-582). The therapeutical effects of mibefradil and the L-type and T-type dual calcium ion channel blocker efonidipine further demonstrated the above inference (Cardiovascular Drug Reviews, 2002, 20(1):81-92). However, due to the drug interaction, mibefradil was withdrawn from the market less than one year after it was put into the market. Therefore, it is clinically urgent to develop compounds having better safety and dual blocking effects on L-type and T-type calcium ion channels. The blocking effect on both L-type calcium ion channels and T-type calcium ion channels can not only provide the utility of treating high blood pressure and solve the side effects that are insuperable for the L-type calcium ion channel blockers, but also exert the protective effect on heart and kidney.